http://www.raredr.com/news/vertex-positive-data-in-cystic-fibrosis
Vertex Stock Soars Following Positive Data from 3 Different Regimens in Cystic Fibrosis Patients

Mathew Shanley

On Tuesday, Vertex Pharmaceuticals announced positive data from Phase 1 and Phase 2 studies of three different triple combination regimens in people with cystic fibrosis (CF) who have one F508del mutation and one minimal function mutation (F508del/Min).
 
These are the first data to exhibit the possibility of treating the underlying cause of CF patients with these specific mutations. It has previously been difficult to treat these severe cases of the disease. The results of these studies are so compelling that Vertex stock has risen over 22% in the past 24 hours, adding over $8 billion to its market value.  
 
Cystic fibrosis is a hereditary, potentially-fatal condition that causes damage to the lungs and digestive system. Its primary roots are defects in a single gene known as the cystic fibrosis transmembrane conductance regulator, or CFTR. Common symptoms include lung infections, coughing and difficulty breathing. Approximately 75,000 people in North America, Europe and Australia are affected by it.
 
In most cases, treatment options are limited to management of the associated symptoms, although Vertex has previously been granted approval for its drugs Kalydeco (ivacaftor) and Orkami (lumacaftor and ivacaftor) in select groups of CF patients with particular CFTR mutations. The new data with the triple drug combinations provides options for additional CF patients.
 
“These safety and efficacy data are clear and compelling, indicating significant potential benefit for people with CF from each of these three different triple combination regimens,” said Jeffrey Chodakewitz, M.D., Executive Vice President and Chief Medical Officer at Vertex in a press release. “We will be collecting and evaluating additional data from these and other studies and will make a decision on which regimen(s) to take forward into pivotal program(s), which we expect to begin in the first half of 2018.”
 
The VX-440 Phase 2 Study was a randomized, double-blind trial that evaluated VX-440 (200mg and 600mg q12h) in combination with tezacaftor and ivacaftor in two different groups of people with CF ages 18 and older. The first group included patients with 1 F508del mutation and 1 minimal function mutation, and the second group had 2 copies of the F508del mutation. The primary objectives for the study were safety, tolerability and efficacy. The triple combination regimen was generally well-tolerated, with most adverse events being mild or moderate cases of infective pulmonary exacerbation, cough, sputum increased and diarrhea.
 
Secondary endpoints of the study include change in sweat chloride and Cystic Fibrosis Questionnaire-Revised (CFQ-R). A summary of the within-group lung function and sweat chloride data for the triple combination treatment period, from baseline (end of the 4-week tezacaftor/ivacaftor run-in period), is provided below:

VX-440 in F508del/Min Patients

Mean Absolute Within-Group Change From Baseline Through Day 29*  

Mean Absolute Within-Group Change in ppFEV(percentage points)

 

Mean Absolute Within-Group Change in Sweat Chloride (mmol/L)

Triple placebo   +1.4

(p=0.4908)

  +1.6

(p=0.6800)

VX-440 (200mg q12h) + tezacaftor (50mg q12h or 100mg QD) + ivacaftor (150mg q12h)   +10.0

(p<0.0001)

  -20.7

(p<0.0001)

VX-440 (600mg q12h) + tezacaftor (50mg q12h) + ivacaftor (300mg q12h)   +12.0

(p<0.0001)

  -33.1

(p<0.0001)

* all p-values are within group p-values based on mixed effect models; values expressed as ‘Through Day 29’ are the average of Day 15 and Day 29 measures


The VX-152 Phase 2 Study is also randomized and double-blind, but evaluated VX-152 in combination with tezacaftor and ivacaftor in CF patients 18 years and older who have 1 F508del mutation and 1 minimal function mutation and in people who have 2 copies of the F508del mutation. The study’s primary objective is safety and tolerability, and the triple combination regimen was generally well-tolerated. Mild or moderate adverse events that occurred included cough, sputum increased, infective pulmonary exacerbation, productive cough, diarrhea and fatigue.
 
Secondary endpoints include mean absolute variation in ppFEV1 and alteration in sweat chloride. A summary of the initial within-group lung function and sweat chloride data (secondary endpoints) from the VX-152 100mg and 200mg dose groups is provided below:

VX-440 in F508del/F508del Patients

Mean Absolute Within-Group Change From Baseline Through Day 29*   Mean Absolute Within-Group Change in ppFEV1 (percentage points)   Mean Absolute Within-Group Change in Sweat Chloride (mmol/L)
Placebo + tezacaftor (100mg QD) + ivacaftor (150mg q12h)   -2.5

(p=0.2755)

  +2.1

(p=0.7385)

VX-440 (600mg q12h) + tezacaftor (50mg q12h) + ivacaftor (300mg q12h)   +9.5

(p<0.0001)

  -31.3

(p<0.0001)

* all p-values are within group p-values based on mixed effect models; values expressed as ‘Through Day 29’ are the average of Day 15 and Day 29 measures

 
The Phase 1 randomized, double-blind, placebo-controlled study assessed the safety and tolerability of single and multiple increasing doses of VX-659 by itself and also in triple combination with tezacaftor and ivacaftor in healthy volunteers. Twelve CF patients ages 18 and older who have one F508del mutation and one minimal function mutation were also studied for 2 weeks to assess the safety and tolerability of VX-659 as part of a triple combination.
 
VX-659 was mostly well-tolerated in triple combination with tezacaftor and ivacaftor in CF patients, and at Day 15, there was an absolute improvement in ppFEV1 in those receiving the triple combination regimen of VX-659, tezacaftor and ivacaftor with a mean decrease in sweat chloride. For those receiving placebo, there was a mean absolute decrease in ppFEV1 and a mean decrease in sweat chloride, as well.
 
“Patients with minimal function mutations have been waiting for a medicine to treat the underlying cause of their disease, which makes these data showing pronounced improvements in lung function particularly important,” said Steven M. Rowe, M.D., M.S.P.H., Professor of Medicine, Pediatrics, and Cell, Developmental and Integrative Biology, Director of the Gregory Fleming James Cystic Fibrosis Research Center, Nancy and Eugene Gwaltney Endowed Chair for Medical Research, University of Alabama at Birmingham.
 
“It’s also encouraging to see that the addition of a next-generation corrector may lead to substantial additional benefits for patients with two copies of the F508del mutation, who were already receiving tezacaftor and ivacaftor.”
 
Vertex has accelerated the development programs for both VX-445 and VX-659, and next steps include the company’s plans to begin fundamental development of 1 or more triple combination regimens in the first half of 2018.
 
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